Optically active fluorine-containing compounds and processes for their production

ABSTRACT

An optically active fluorine-containing compound represented by the following formula (1):  
                 
 
     wherein A is an oxygen atom, a sulfur atom or an NH group, and R 1  is a methyl group, an ethyl group, a C 3-10  linear, branched or cyclic alkyl group, a C 6-20  aromatic group, a C 6-20  aromatic group having hydrogen on the aromatic ring optionally substituted by a halogen atom, a C 6-20  aromatic group having hydrogen on the aromatic ring optionally substituted by a methyl group, a C 6-20  aromatic group having hydrogen on the aromatic ring optionally substituted by an ethyl group, a C 6-20  aromatic group having hydrogen on the aromatic ring optionally substituted by a C 3-6  linear, branched or cyclic alkyl group, a C 6-20  aromatic group having hydrogen on the aromatic ring optionally substituted by a methoxy group, a C 6-20  aromatic group having hydrogen on the aromatic ring optionally substituted by an ethoxy group, a C 6-20  aromatic group having hydrogen on the aromatic ring optionally substituted by a C 3-6  linear, branched or cyclic alkyloxy group, a C 5-19  heteroaromatic group, a C 5-19  heteroaromatic group having hydrogen on the aromatic ring optionally substituted by a halogen atom, a C 5-19  heteroaromatic group having hydrogen on the aromatic ring optionally substituted by a methyl group, a C 5-19  heteroaromatic group having hydrogen on the aromatic ring optionally substituted by an ethyl group, a C 5-19  heteroaromatic group having hydrogen on the aromatic ring optionally substituted by a C 3-6  linear, branched or cyclic alkyl group, a C 5-19  heteroaromatic group having hydrogen on the aromatic ring optionally substituted by a methoxy group, a C 5-19  heteroaromatic group having hydrogen on the aromatic ring optionally substituted by an ethoxy group, a C 5-19  heteroaromatic group having hydrogen on the aromatic ring optionally substituted by a C 3-6  linear, branched or cyclic alkyloxy group, a benzyl group, a benzyl group having hydrogen on the aromatic ring optionally substituted by a halogen atom, a benzyl group having hydrogen on the aromatic ring optionally substituted by a methyl group, a benzyl group having hydrogen on the aromatic ring optionally substituted by an ethyl group, a benzyl group having hydrogen on the aromatic ring optionally substituted by a C 3-6  linear, branched or cyclic alkyl group, a 2-phenylethyl group, or a C 3-10  linear, branched or cyclic alkyl group having a C 6-20  aromatic group bonded thereto, or by the following formula ( 2 ):  
                 
 
     wherein A and R 1  are as defined above.

[0001] The present invention relates to optically activefluorine-containing novel compounds, processes for their production, andprocesses for producing optically active3,3,3-trifluoro-2-hydroxy-2-methylpropionic acids, employing them.

[0002] The optically active fluorine-containing compounds of the presentinvention are compounds useful as intermediates for pharmaceuticals oragricultural chemicals. For example, an optically active benzyl ester of2,3-epoxy-α,α,α,-trifluoropropionic acid as one of such compounds, canreadily be led to optically active3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid which is known as acompound very useful as an intermediate for pharmaceuticals oragricultural chemical.

[0003] As a process for producing optically active3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid, a production method byoptical resolution of racemic3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid by means of e.g.optically active α-phenylethylamine, has, for example, been known (e.g.JP-A-5-286915, J. Chem. Soc., 2329-2332, 1951, or J. Med. Chem., 39,4592-4601, 1996).

[0004] Further, a process is known wherein racemic3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid ester derivative ishydrolyzed by means of lipase to produce optically active3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (e.g. WO97/38124).

[0005] However, the production process employing an optical resolutionagent, has a problem in the efficiency, since it is necessary to repeatrecrystallization at least few times, and it is required to carry out atreatment to remove the optical resolution agent.

[0006] Further, in the process employing lipase, it is not possible toracemize the unnecessary optical antipode and to reuse it as a startingmaterial, at the time of producing3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid. Thus, such a processcan not be regarded as an advantageous process.

[0007] Further, no process has been known in which optically active3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid is produced efficientlyby an asymmetric synthesis.

[0008] The present inventors have conducted an extensive study on aprocess for producing optically active3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid to solve theabove-mentioned problems and as a result, have found that an opticallyactive benzyl ester of 2,3-epoxy-α,α,α,-trifluoropropionic acid can beled to a novel optically active 2,3-epoxy-α,α,α,-trifluoropropionic acidby a hydrogenation reaction, and further that by reacting such acompound with a metal hydride, optically active3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid can be produced easilyand efficiently. Further, they have been found that novel opticallyactive fluorine-containing compounds including the optically activebenzyl ester of 2,3-epoxy-α,α,α,-trifluoropropionic acid, can beobtained by asymmetrically epoxidizing specificα,α,α,-trifluoromethacrylic acid derivatives. The present invention hasbeen accomplished on the basis of these discoveries.

[0009] Namely, the present invention provides:

[0010] 1. An optically active fluorine-containing compound representedby the following formula (1):

[0011] wherein A is an oxygen atom, a sulfur atom or an NH group, and R¹is a methyl group, an ethyl group, a C₃₋₁₀ linear, branched or cyclicalkyl group, a C₆₋₂₀ aromatic group, a C₆₋₂₀ aromatic group havinghydrogen on the aromatic ring optionally substituted by a halogen atom,a C₆₋₂₀ aromatic group having hydrogen on the aromatic ring optionallysubstituted by a methyl group, a C₆₋₂₀ aromatic group having hydrogen onthe aromatic ring optionally substituted by an ethyl group, a C₆₋₂₀aromatic group having hydrogen on the aromatic ring optionallysubstituted by a C₃₋₆ linear, branched or cyclic alkyl group, a C₆₋₂₀aromatic group having hydrogen on the aromatic ring optionallysubstituted by a methoxy group, a C₆₋₂₀ aromatic group having hydrogenon the aromatic ring optionally substituted by an ethoxy group, a C₆₋₂₀aromatic group having hydrogen on the aromatic ring optionallysubstituted by a C₃₋₆ linear, branched or cyclic alkyloxy group, a C₅₋₁₉heteroaromatic group, a C₅₋₁₉ heteroaromatic group having hydrogen onthe aromatic ring optionally substituted by a halogen atom, a C₅₋₁₉heteroaromatic group having hydrogen on the aromatic ring optionallysubstituted by a methyl group, a C₅₋₁₉ heteroaromatic group havinghydrogen on the aromatic ring optionally substituted by an ethyl group,a C₅₋₁₉ heteroaromatic group having hydrogen on the aromatic ringoptionally substituted by a C₃₋₆ linear, branched or cyclic alkyl group,a C₅₋₁₉ heteroaromatic group having hydrogen on the aromatic ringoptionally substituted by a methoxy group, a C₅₋₁₉ heteroaromatic grouphaving hydrogen on the aromatic ring optionally substituted by an ethoxygroup, a C₅₋₁₉ heteroaromatic group having hydrogen on the aromatic ringoptionally substituted by a C₃₋₆ linear, branched or cyclic alkyloxygroup, a benzyl group, a benzyl group having hydrogen on the aromaticring optionally substituted by a halogen atom, a benzyl group havinghydrogen on the aromatic ring optionally substituted by a methyl group,a benzyl group having hydrogen on the aromatic ring optionallysubstituted by an ethyl group, a benzyl group having hydrogen on thearomatic ring optionally substituted by a C₃₋₆ linear, branched orcyclic alkyl group, a 2-phenylethyl group, or a C₃₋₁₀ linear, branchedor cyclic alkyl group having a C₆₋₂₀ aromatic group bonded thereto, orby the following formula (2):

[0012] wherein A and R¹ are as defined above.

[0013] 2. An optically active fluorine-containing compound representedby the following formula (3) or (4):

[0014] 3. A process for producing an optically activefluorine-containing compound represented by the above formula (1) or(2), which comprises asymmetrically epoxidizing anα,α,α,-trifluoromethacrylic acid derivative represented by the followingformula (5):

[0015] wherein A is an oxygen atom, a sulfur atom or an NH group, and R¹is a methyl group, an ethyl group, a C₃₋₁₀ linear, branched or cyclicalkyl group, a C₆₋₂₀ aromatic group, a C₆₋₂₀ aromatic group havinghydrogen on the aromatic ring optionally substituted by a halogen atom,a C₆₋₂₀ aromatic group having hydrogen on the aromatic ring optionallysubstituted by a methyl group, a C₆₋₂₀ aromatic group having hydrogen onthe aromatic ring optionally substituted by an ethyl group, a C₆₋₂₀aromatic group having hydrogen on the aromatic ring optionallysubstituted by a C₃₋₆ linear, branched or cyclic alkyl group, a C₆₋₂₀aromatic group having hydrogen on the aromatic ring optionallysubstituted by a methoxy group, a C₆₋₂₀ aromatic group having hydrogenon the aromatic ring optionally substituted by an ethoxy group, a C₆₋₂₀aromatic group having hydrogen on the aromatic ring optionallysubstituted by a C₃₋₆ linear, branched or cyclic alkyloxy group, a C₅₋₁₉heteroaromatic group, a C₅₋₁₉ heteroaromatic group having hydrogen onthe aromatic ring optionally substituted by a halogen atom, a C₅₋₁₉heteroaromatic group having hydrogen on the aromatic ring optionallysubstituted by a methyl group, a C₅₋₁₉ heteroaromatic group havinghydrogen on the aromatic ring optionally substituted by an ethyl group,a C₅₋₁₉ heteroaromatic group having hydrogen on the aromatic ringoptionally substituted by a C₃₋₆ linear, branched or cyclic alkyl group,a C₅₋₁₉ heteroaromatic group having hydrogen on the aromatic ringoptionally substituted by a methoxy group, a C₅₋₁₉ heteroaromatic grouphaving hydrogen on the aromatic ring optionally substituted by an ethoxygroup, a C₅₋₁₉ heteroaromatic group having hydrogen on the aromatic ringoptionally substituted by a C₃₋₆ linear, branched or cyclic alkyloxygroup, a benzyl group, a benzyl group having hydrogen on the aromaticring optionally substituted by a halogen atom, a benzyl group havinghydrogen on the aromatic ring optionally substituted by a methyl group,a benzyl group having hydrogen on the aromatic ring optionallysubstituted by an ethyl group, a benzyl group having hydrogen on thearomatic ring optionally substituted by a C₃₋₆ linear, branched orcyclic alkyl group, a 2-phenylethyl group, or a C₃₋₁₀ linear, branchedor cyclic alkyl group having a C₆₋₂₀ aromatic group bonded thereto.

[0016] 4. The process for producing an optically activefluorine-containing compound represented by the above formula (1) or(2), wherein the α,α,α,-trifluoromethacrylic acid derivative representedby the formula (5) is subjected to the asymmetric epoxidizing reactionin the presence of a catalyst comprising (A) a rare earth metalalkoxide, (B) optically active 1,1′-bi-2-naphthol, (C)triphenylphosphine oxide and (D) cumene hydroperoxide or tert-butylhydroperoxide.

[0017] 5. An optically active fluorine-containing compound representedby the following formula (6) or (7):

[0018] 6. A process for producing the optically activefluorine-containing compound represented by the above formula (6), whichcomprises hydrolyzing or hydrogenating the optically activefluorine-containing compound represented by the above formula (3).

[0019] 7. A process for producing the optically activefluorine-containing compound represented by the above formula (7), whichcomprises hydrolyzing or hydrogenating an optically activefluorine-containing compound represented by the above formula (4).

[0020] 8. A process for producing(R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid, which comprisesreacting the optically active fluorine-containing compound representedby the above formula (6), with a metal hydride.

[0021] 9. A process for producing(S)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid, which comprisesreacting the optically active fluorine-containing compound representedby the above formula (7), with a metal hydride.

[0022] Now, the present invention will be described in detail.

[0023] The optically active fluorine-containing compound represented bythe above formula (1) or (2) of the present invention, can be producedby asymmetrically epoxidizing the α,α,α, -trifluoromethacrylic acidderivative represented by the above formula (5).

[0024] In the present invention, in the above formula (1), (2) or (5), Arepresents an oxygen atom, a sulfur atom or an NH group. Among them, anoxygen atom is preferred as A.

[0025] Further, in the present invention, in the above formula (1), (2)or (5), R¹ is a methyl group, an ethyl group, a C₃₋₁₀ linear, branchedor cyclic alkyl group, a C₆₋₂₀ aromatic group, a C₆₋₂₀ aromatic grouphaving hydrogen on the aromatic ring optionally substituted by a halogenatom, a C₆₋₂₀ aromatic group having hydrogen on the aromatic ringoptionally substituted by a methyl group, a C₆₋₂₀ aromatic group havinghydrogen on the aromatic ring optionally substituted by an ethyl group,a C₆₋₂₀ aromatic group having hydrogen on the aromatic ring optionallysubstituted by a C₃₋₆ linear, branched or cyclic alkyl group, a C₆₋₂₀aromatic group having hydrogen on the aromatic ring optionallysubstituted by a methoxy group, a C₆₋₂₀ aromatic group having hydrogenon the aromatic ring optionally substituted by an ethoxy group, a C₆₋₂₀aromatic group having hydrogen on the aromatic ring optionallysubstituted by a C₃₋₆ linear, branched or cyclic alkyloxy group, a C₅₋₁₉heteroaromatic group, a C₅₋₁₉ heteroaromatic group having hydrogen onthe aromatic ring optionally substituted by a halogen atom, a C₅₋₁₉heteroaromatic group having hydrogen on the aromatic ring optionallysubstituted by a methyl group, a C₅₋₁₉ heteroaromatic group havinghydrogen on the aromatic ring optionally substituted by an ethyl group,a C₅₋₁₉ heteroaromatic group having hydrogen on the aromatic ringoptionally substituted by a C₃₋₆ linear, branched or cyclic alkyl group,a C₅₋₁₉ heteroaromatic group having hydrogen on the aromatic ringoptionally substituted by a methoxy group, a C₅₋₁₉ heteroaromatic grouphaving hydrogen on the aromatic ring optionally substituted by an ethoxygroup, a C₅₋₁₉ heteroaromatic group having hydrogen on the aromatic ringoptionally substituted by a C₃₋₆ linear, branched or cyclic alkyloxygroup, a benzyl group, a benzyl group having hydrogen on the aromaticring optionally substituted by a halogen atom, a benzyl group havinghydrogen on the aromatic ring optionally substituted by a methyl group,a benzyl group having hydrogen on the aromatic ring optionallysubstituted by an ethyl group, a benzyl group having hydrogen on thearomatic ring optionally substituted by a C₃₋₆ linear, branched orcyclic alkyl group, a 2-phenylethyl group, or a C₃₋₁₀ linear, branchedor cyclic alkyl group having a C₆₋₂₀ aromatic group bonded thereto.Among them, R¹ is preferably a tert-butyl group, a phenyl group, aphenyl group having hydrogen on the aromatic ring substituted by ahalogen atom, or a benzyl group, particularly preferably a benzyl group.

[0026] The compound represented by the above formula (1) or (2) of thepresent invention is not particularly limited, but specifically, thecompound wherein A is an oxygen atom, and R¹ is a C₁₋₁₀ alkyl group may,for example, be (R)-2,3-epoxy-2-(trifluoromethyl)propionic acid methylester, (R)-2,3-epoxy-2-(trifluoromethyl)propionic acid ethyl ester,(R)-2,3-epoxy-2-(trifluoromethyl)propionic acid isopropyl ester,(R)-2,3-epoxy-2-(trifluoromethyl)propionic acid n-butyl ester,(R)-2,3-epoxy-2-(trifluoromethyl)propionic acid n-butyl ester,(R)-2,3-epoxy-2-(trifluoromethyl)propionic acid tert-butyl ester,(R)-2,3-epoxy-2-(trifluoromethyl)propionic acid cyclohexyl ester,(R)-2,3-epoxy-2-(trifluoromethyl)propionic acid cyclohexylmethyl esteror (R)-2,3-epoxy-2-(trifluoromethyl)propionic acid 2-cyclohexylethylester.

[0027] Further, the compound represented by the above formula (1) or (2)wherein A is an oxygen atom, and R¹ is a C₆₋₂₀ aromatic group, may, forexample, be (R)-2,3-epoxy-2-(trifluoromethyl)propionic acid phenylester, (R)-2,3-epoxy-2-(trifluoromethyl)propionic acid p-chlorophenylester, (R)-2,3-epoxy-2-(trifluoromethyl)propionic acid m-chlorophenylester, (R)-2,3-epoxy-2-(trifluoromethyl)propionic acid o-chlorophenylester, (R)-2,3-epoxy-2-(trifluoromethyl)propionic acid p-bromophenylester, (R)-2,3-epoxy-2-(trifluoromethyl)propionic acid m-bromophenylester, (R)-2,3-epoxy-2-(trifluoromethyl)propionic acid o-bromophenylester, (R)-2,3-epoxy-2-(trifluoromethyl)propionic acid p-fluorophenylester, (R)-2,3-epoxy-2-(trifluoromethyl)propionic acid m-fluorophenylester, (R)-2,3-epoxy-2-(trifluoromethyl)propionic acid o-fluorophenylester, (R)-2,3-epoxy-2-(trifluoromethyl)propionic acid p-methoxyphenylester, (R)-2,3-epoxy-2-(trifluoromethyl)propionic acid m-methoxyphenylester or (R)-2,3-epoxy-2-(trifluoromethyl)propionic acid o-methoxyphenylester.

[0028] Further, the compound represented by the above formula (1) or (2)wherein A is an oxygen atom, and R¹ is a C₁₋₁₀ alkyl group having aC₆₋₂₀ aromatic group bonded thereto, may, for example, be(R)-2,3-epoxy-2-(trifluoromethyl)propionic acid benzyl ester,(R)-2,3-epoxy-2-(trifluoromethyl)propionic acid 2-phenylethyl ester,(R)-2,3-epoxy-2-(trifluoromethyl)propionic acid (p-chlorophenyl)methylester, (R)-2,3-epoxy-2-(trifluoromethyl)propionic acid(p-bromophenyl)methyl ester or(R)-2,3-epoxy-2-(trifluoromethyl)propionic acid (p-fluorophenyl)methylester.

[0029] Further, the compound represented by the above formula (1) or (2)wherein A is an NH group and R¹ is a C₁₋₁₀ alkyl group, may, forexample, be (R)-2,3-epoxy-2-(trifluoromethyl)propionic acid methylamide,(R)-2,3-epoxy-2-(trifluoromethyl)propionic acid ethylamide,(R)-2,3-epoxy-2-(trifluoromethyl)propionic acid isopropylamide,(R)-2,3-epoxy-2-(trifluoromethyl)propionic acid n-butylamide,(R)-2,3-epoxy-2-(trifluoromethyl)propionic acid n-butylamide,(R)-2,3-epoxy-2-(trifluoromethyl)propionic acid tert-butylamide,(R)-2,3-epoxy-2-(trifluoromethyl)propionic acid cyclohexylamide,(R)-2,3-epoxy-2-(trifluoromethyl)propionic acid cyclohexylmethylamide or(R)-2,3-epoxy-2-(trifluoromethyl)propionic acid 2-cyclohexylethylamide.

[0030] Further, the compound represented by the above formula (1) or (2)wherein A is an NH group and R¹ is a C₆₋₂₀ aromatic group, may, forexample, be (R)-2,3-epoxy-2-(trifluoromethyl)propionic acid anilide,(R)-2,3-epoxy-2-(trifluoromethyl)propionic acid p-chlorophenylamide,(R)-2,3-epoxy-2-(trifluoromethyl)propionic acid m-chlorophenylamide,(R)-2,3-epoxy-2-(trifluoromethyl)propionic acid o-chlorophenylamide,(R)-2,3-epoxy-2-(trifluoromethyl)propionic acid, p-bromophenylamide,(R)-2,3-epoxy-2-(trifluoromethyl)propionic acid m-bromophenylamide,(R)-2,3-epoxy-2-(trifluoromethyl)propionic acid o-bromophenylamide,(R)-2,3-epoxy-2-(trifluoromethyl)propionic acid p-fluorophenylamide,(R)-2,3-epoxy-2-(trifluoromethyl)propionic acid m-fluorophenylamide,(R)-2,3-epoxy-2-(trifluoromethyl)propionic acid o-fluorophenylamide,(R)-2,3-epoxy-2-(trifluoromethyl)propionic acid p-methoxyphenylamide,(R)-2,3-epoxy-2-(trifluoromethyl)propionic acid m-methoxyphenylamide or(R)-2,3-epoxy-2-(trifluoromethyl)propionic acid o-methoxyphenylamide.

[0031] Further, the compound represented by the above formula (1) or (2)wherein A is an NH group, and R¹ is a C₁₋₁₀ alkyl group having a C₆₋₂₀aromatic group bonded thereto, may, for example, be(R)-2,3-epoxy-2-(trifluoromethyl)propionic acid benzylamide,(R)-2,3-epoxy-2-(trifluoromethyl)propionic acid 2-phenylethylamide,(R)-2,3-epoxy-2-(trifluoromethyl)propionic acid(p-chlorophenyl)methylamide, (R)-2,3-epoxy-2-(trifluoromethyl)propionicacid (p-bromophenyl)methylamide or(R)-2,3-epoxy-2-(trifluoromethyl)propionic acid(p-fluorophenyl)methylamide.

[0032] The compound represented by the above formula (1) or (2) of thepresent invention includes not only the above-mentioned such (R)isomers, but also (S) isomers which are antipodes of the (R) isomers. Inthe present invention, it is possible to produce the optically activefluorine-containing compound represented by the above formula (1) or (2)by asymmetrically epoxidizing an α,α,α-trifluoromethacrylic acidderivative represented by the above formula (5).

[0033] The compound represented by the above formula (5) of the presentinvention is not particularly limited, but specifically, the compoundwherein A is an oxygen atom, and R¹ is a C₁₋₁₀ alkyl group, may, forexample, be α,α,α-trifluoromethacrylic acid methyl ester,α,α,α-trifluoromethacrylic acid ethyl ester, α,α,α-trifluoromethacrylicacid isopropyl ester, α,α,α-trifluoromethacrylic acid n-butyl ester,α,α,α-trifluoromethacrylic acid n-butyl ester,α,α,α-trifluoromethacrylic acid tert-butyl ester,α,α,α-trifluoromethacrylic acid cyclohexyl ester,α,α,α-trifluoromethacrylic acid cyclohexylmethyl ester orα,α,α-trifluoromethacrylic acid 2-cyclohexylethyl ester.

[0034] Further, the compound represented by the above formula (5)wherein A is an oxygen atom, and R¹ is a C₆₋₂₀ aromatic group, may, forexample, be α,α,α-trifluoromethacrylic acid phenyl ester,α,α,α-trifluoromethacrylic acid p-chlorophenyl ester,α,α,α-trifluoromethacrylic acid m-chlorophenyl ester,α,α,α-trifluoromethacrylic acid o-chlorophenyl ester,α,α,α-trifluoromethacrylic acid p-bromophenyl ester,α,α,α-trifluoromethacrylic acid m-bromophenyl ester,α,α,α-trifluoromethacrylic acid o-bromophenyl ester,α,α,α-trifluoromethacrylic acid p-fluorophenyl ester,α,α,α-trifluoromethacrylic acid m-fluorophenyl ester,α,α,α-trifluoromethacrylic acid o-fluorophenyl ester,α,α,α-trifluoromethacrylic acid p-methoxyphenyl ester,α,α,α-trifluoromethacrylic acid m-methoxyphenyl ester orα,α,α-trifluoromethacrylic acid o-methoxyphenyl ester.

[0035] Further, the compound represented by the above formula (5)wherein A is an oxygen atom, and R¹ is a C₁₋₁₀ alkyl group having aC₆₋₂₀ aromatic group bonded thereto, may, for example, beα,α,α-trifluoromethacrylic acid benzyl ester, α,α,α-trifluoromethacrylicacid 2-phenylethyl ester, α,α,α-trifluoromethacrylic acid(p-chlorophenyl)methyl ester, α,α,α-trifluoromethacrylic acid(p-bromophenyl)methyl ester or α,α,α-trifluoromethacrylic acid(p-fluorophenyl)methyl ester.

[0036] Further, the compound represented by the above formula (5)wherein A is an NH group, and R¹ is a C₁₋₁₀ alkyl group, may, forexample, be α,α,α-trifluoromethacrylic acid methylamide,α,α,α-trifluoromethacrylic acid ethylamide, α,α,α-trifluoromethacrylicacid isopropylamide, α,α,α-trifluoromethacrylic acid n-butylamide,α,α,α-trifluoromethacrylic acid n-butylamide, α,α,α-trifluoromethacrylicacid tert-butylamide, α,α,α-trifluoromethacrylic acid cyclohexyl amide,α,α,α-trifluoromethacrylic acid cyclohexyl methylamide orα,α,α-trifluoromethacrylic acid 2-cyclohexyl ethylamide.

[0037] Further, the compound represented by the above formula (3)wherein A is an NH group, and R¹ is a C₆₋₂₀ aromatic group, may, forexample, be α,α,α-trifluoromethacrylic acid anilide,α,α,α-trifluoromethacrylic acid p-chlorophenylamide,α,α,α-trifluoromethacrylic acid m-chlorophenylamide,α,α,α-trifluoromethacrylic acid o-chlorophenylamide,α,α,α-trifluoromethacrylic acid p-bromophenylamide,α,α,α-trifluoromethacrylic acid m-bromophenylamide,α,α,α-trifluoromethacrylic acid o-bromophenylamide,α,α,α-trifluoromethacrylic acid p-fluorophenylamide,α,α,α-trifluoromethacrylic acid m-fluorophenylamide,α,α,α-trifluoromethacrylic acid o-fluorophenylamide,α,α,α-trifluoromethacrylic acid p-methoxyphenylamide,α,α,α-trifluoromethacrylic acid m-methoxyphenylamide orα,α,α-trifluoromethacrylic acid o-methoxyphenylamide.

[0038] Further, the compound represented by the above formula (5)wherein A is an NH group, and R¹ is a C₁₋₁₀ alkyl group having a C₆₋₂₀aromatic group bonded thereto, may, for example, beα,α,α-trifluoromethacrylic acid benzylamide, α,α,α,-trifluoromethacrylicacid 2-phenylethylamide, α,α,α-trifluoromethacrylic acid(p-chlorophenyl)methylamide, α,α,α-trifluoromethacrylic acid(p-bromophenyl)methylamide or α,α,α-trifluoromethacrylic acid(p-fluorophenyl)methylamide.

[0039] In the process of the present invention, a method for preparingthe α,α,α-trifluoromethacrylic acid derivative represented by the aboveformula (5) is not particularly limited. However, it may be prepared,for example, by treating α,α,α-trifluoromethacrylic acid with thionylchloride to obtain α,α,α-trifluoromethacrylic acid chloride, which isthen reacted with an alcohol represented by R1-A-H, a phenol and anamine in the presence of a base such as triethylamine in a solvent suchas diethyl ether or dichloromethane.

[0040] In the process of the present invention, various asymmetricepoxidizing reactions may be used for the preparation of the opticallyactive fluorine-containing compound represented by the above formula (1)or (2). For example, a method of employing titanium tetraisopropoxide ora tartaric acid derivative, a method of employing a quaternary ammoniumsalt such as a cinchona alkaloid derivative, a method of employing ametal such as zinc, lithium, magnesium or a lanthanoid, or an asymmetricligand of e.g. an optically active 1,1′-bi-2-naphthol derivative, amethod of employing an optically active dioxirane, or a method ofemploying a salen-manganese complex, may, for example, be mentioned.However, in the process of the present invention, it is preferred tocarry out the asymmetric epoxidizing reaction in the presence of acatalyst comprising (A) a rare earth metal alkoxide, (B) opticallyactive 1,1′-bi-2-naphthol, (C) triphenylphosphine oxide, and (D) cumenehydroperoxide or tert-butyl hydroperoxide.

[0041] In the process of the present invention, (A) the rare earth metalalkoxide to be used for the asymmetric epoxidizing reaction, is notparticularly limited. However, specifically, it may, for example, bescandium trimethoxide, scandium triethoxide, scandium triisopropoxide,scandium tri-n-propoxide, yttrium trimethoxide, yttrium triethoxide,yttrium triisopropoxide, yttrium tri-n-propoxide, lanthanumtrimethoxide, lanthanum triethoxide, lanthanum triisopropoxide,lanthanum tri-n-propoxide, cerium trimethoxide, cerium triethoxide,cerium triisopropoxide, cerium tri-n-propoxide, praseodymiumtrimethoxide, praseodymium triethoxide, praseodymium triisopropoxide,praseodymium tri-n-propoxide, neodymium trimethoxide, neodymiumtriethoxide, neodymium triisopropoxide, neodymium tri-n-propoxide,samarium trimethoxide, samarium triethoxide, samarium triisopropoxide,samarium tri-n-propoxide, europium trimethoxide, europium triethoxide,europium triisopropoxide, europium tri-n-propoxide, gadoliniumtrimethoxide, gadolinium triethoxide, gadolinium triisopropoxide,gadolinium tri-n-propoxide, terbium trimethoxide, terbium triethoxide,terbium triisopropoxide, terbium tri-n-propoxide, dysprosiumtrimethoxide, dysprosium triethoxide, dysprosium triisopropoxide,dysprosium tri-n-propoxide, holmium trimethoxide, holmium triethoxide,holmium triisopropoxide, holmium tri-n-propoxide, erbium trimethoxide,erbium triethoxide, erbium triisopropoxide, erbium tri-n-propoxide,thulium trimethoxide, thulium triethoxide, thulium triisopropoxide,thulium tri-n-propoxide, ytterbium trimethoxide, ytterbium triethoxide,ytterbium triisopropoxide, ytterbium tri-n-propoxide, rutheniumtrimethoxide, ruthenium triethoxide, ruthenium triisopropoxide orruthenium tri-n-propoxide.

[0042] In the process of the present invention, (A) the rare earth metalalkoxide is preferably a lanthanoid triisopropoxide such as lanthanumtriisopropoxide, cerium triisopropoxide, praseodymium triisopropoxide,neodymium triisopropoxide, samarium triisopropoxide, europiumtriisopropoxide, gadolinium triisopropoxide, terbium triisopropoxide,dysprosium triisopropoxide, holmium triisopropoxide, erbiumtriisopropoxide, thulium triisopropoxide, ytterbium triisopropoxide orruthenium triisopropoxide. Among them, lanthanum triisopropoxide orytterbium triisopropoxide is further preferred, and lanthanumtriisopropoxide is particularly preferred.

[0043] In the process of the present invention, method of preparing therare earth metal alkoxide is not particularly limited. Further, withrespect to the amount of the rare earth metal alkoxide, it is usedusually in an amount of from 0.1 mol % to 30 mol % to theα,α,α-trifluoromethacrylic acid benzyl ester to be used in the presentinvention.

[0044] In the process of the present invention, the amount of theoptically active 1,1′-bi-2-naphthol to be used for the asymmetricepoxidizing reaction is usually from 1 to 2 times by mol, preferablyfrom 1 to 1.2 times by mol, to the lanthanoid triisopropoxide to be usedfor the reaction.

[0045] In the process of the present invention, the amount of thetriphenylphosphine oxide to be used for the asymmetric epoxidizingreaction, is usually from 1 to 5 times by mol, preferably from 1.1 to 3times by mol, to the lanthanoid triisopropoxide to be used for thereaction.

[0046] In the process of the present invention, the amount of cumenehydroperoxide or tert-butyl hydroperoxide to be used for the asymmetricepoxidizing reaction is usually from 1 to 4 times by mol to thelanthanoid triisopropoxide at the time of forming the catalyst, andfurther, at the time of the reaction, it is used usually in an amount offrom 1 to 2 times by mol to the α,α,α,-trifluoromethacrylic acid benzylester to be used for the reaction.

[0047] In the process of the present invention, for the preparation ofthe optically active fluorine-containing compound represented by theabove formula (1), it is particularly preferred to carry out theasymmetric epoxidizing reaction by cumene hydroperoxide by means of acatalyst comprising (A) a lanthanoid triisopropoxide as the rare earthmetal alkoxide, (B) (R)-1,1′-bi-2-naphthol as the optically active1,1′-bi-2-naphthol, (C) triphenylphosphine oxide and (D) cumenehydroperoxide. Likewise, for the preparation of the optically activefluorine-containing compound represented by the above formula (2), it isparticularly preferred to carry out the asymmetric epoxidizing reactionby cumene hydroperoxide by means of a catalyst comprising (A) alanthanoid triisopropoxide as the rare earth metal alkoxide, (B)(S)-1,1′-bi-2-naphthol as the optically. active 1,1′-bi-2-naphthol, (C)triphenylphosphine oxide and (D) cumene hydroperoxide.

[0048] In the process of the present invention, at the time of theasymmetric epoxidizing reaction, a catalyst solution comprising (A) arare earth metal alkoxide, (B) an optically active 1,1′-bi-2-naphthol,(C) triphenylphosphine oxide and (D) cumene hydroperoxide or tert-butylhydroperoxide, may preliminarily be prepared, and the substrate andcumene hydroperoxide or tert-butyl hydroperoxide are mixed and suppliedto the catalyst solution, to carry out the reaction. Otherwise, thesubstrate and cumene hydroperoxide or tert-butyl hydroperoxide mayrespectively separately supplied to the catalyst solution to carry outthe reaction.

[0049] In the process of the present invention, at the time of theasymmetric epoxidizing reaction, in order to maintain the reactionsystem to be anhydrous, a zeolite such as powdery or molded molecularsieves 3A or molecular sieves 4A may be used in a proper amount, as thecase requires.

[0050] In the process of the present invention, the solvent useful forthe asymmetrical epoxidizing reaction is not particularly limited.However, specifically, it may, for example, be an ether such astetrahydrofuran (hereinafter referred to simply as THF), diethyl etheror diisopropyl ether, or an aromatic hydrocarbon such as benzene,toluene or ethylbenzene. Preferred is an ether, and particularlypreferred is THF.

[0051] In the process of the present invention, with respect to thereaction temperature, the asymmetric epoxidizing reaction can be carriedout within a range of from −50° C. to 50° C. However, in order to obtainthe optically active fluorine-containing compound represented by theabove formula (1) or (2) in a high optical purity, it is preferablycarried out at a temperature of from −30° C. to 10° C.

[0052] In the process of the present invention, the reaction time forthe asymmetric epoxidizing reaction varies depending upon the substrateconcentration, the amount of the catalyst, the concentration of thecatalyst and the reaction temperature and is not particularly limited,but the reaction is usually completed from 2 to 24 hours after addingthe substrate.

[0053] In the process of the present invention, post-treatment after theasymmetric epoxidizing reaction is not particularly limited. Usually,after decomposing the catalyst by adding a saturated ammonium chlorideaqueous solution, excess cumene hydroperoxide is decomposed by e.g. anaqueous sodium hydrogen sulfite solution, followed by purification bye.g. silica gel chromatography, whereby it is possible to obtain the isdesired optically active fluorine-containing compound represented by theabove formula (1) or (2) in an optical purity of from 60 to 95% ee.

[0054] The optically active fluorine-containing compound represented bythe above formula (6) of the present invention can be produced byhydrolyzing the (2R)-2,3-epoxy-2-(trifluoromethyl)propionic acidderivative represented by the above formula (1). Likewise, the opticallyactive fluorine-containing compound represented by the above formula (7)can be produced by hydrolyzing the(2R)-2,3-epoxy-2-(trifluoromethyl)propionic acid derivative representedby the above formula (2).

[0055] The conditions for the hydrolysis of the present invention arenot particularly limited. However, at the time of hydrolysis of theester, an alkali metal hydroxide such as lithium hydroxide, sodiumhydroxide or potassium hydroxide is used in an amount of from 1.2 to 3times by mol to the optically active2,3-epoxy-2-(trifluoromethyl)propionic acid derivative to be reacted,and the reaction is carried out in a mixed solvent of water and methanolwithin a temperature range of from 0 to 60° C. for from 1 to 12 hours,whereby the compound represented by the formula (6) or (7) can beobtained as the desired product. Further, with respect to the hydrolysisof the amide, the reaction is carried out in a solvent in the presenceof from 10 to 100 mol % of hydrochloric acid within a temperature rangeof from 0 to 60° C. for from 1 to 12 hours to obtain the opticallyactive fluorine-containing compound of the above formula (6) or (7) asthe desired product.

[0056] The conditions for post-treatment after the hydrolysis of thepresent invention are not particularly limited, and the desired productis obtained by extraction with a solvent such as ethyl acetate under anacidic condition.

[0057] The optically active fluorine-containing compound represented bythe above formula (6) of the present invention can be produced byhydrogenating (2R)-2,3-epoxy-2-(trifluoromethyl)propionic acid benzylester represented by the above formula (3) in the presence of a metalcatalyst. Likewise, the optically active fluorine-containing compoundrepresented by the above formula (7) can be produced by hydrogenatingthe (2S)-2,3-epoxy-2-(trifluoromethyl)propionic acid benzyl esterrepresented by the above formula (4) in the presence of a metalcatalyst. The metal catalyst to be used for the hydrogenation reactionin the processes of the present invention is not particularly limited.However, specifically, platinum, platinum oxide, palladium, palladiumhydroxide, rhodium, ruthenium, iridium or Raney nickel may, for example,be mentioned. Further, one having such a metal supported on carbon,alumina, calcium sulfate or the like may be mentioned. Preferred isplatinum or platinum oxide.

[0058] The amount of the metal catalyst to be used for the hydrogenationreaction in the processes of the present invention varies depending uponthe type of the catalyst and is not particularly limited. However, it isusually used in an amount of from 0.1 to 20 wt %, as calculated as themetal weight to the optically active2,3-epoxy-2-(trifluoromethyl)propionic acid benzyl ester represented bythe above formula (3) or (4).

[0059] The solvent useful for the hydrogenation reaction in theprocesses of the present invention, is not particularly limited so longas it is inert to the reaction. However, specifically, water, an alcoholsuch as methanol or ethanol, ethyl acetate, acetic acid, an ether,benzene, hexane or dioxane may, for example, be mentioned. Among them,preferred is an alcohol, and methanol is particularly preferred.

[0060] The reaction temperature and the reaction time for thehydrogenation reaction in the processes of the present invention, varydepending upon the type of the catalyst, but usually the reaction willbe completed under atmospheric pressure or an elevated pressure within arange of from −20° C. to 30° C. in from 5 to 24 hours.

[0061] In the processes of the present invention, post-treatment afterthe hydrogenation reaction is not particularly limited. However,usually, after filtering the catalyst off, the solvent is distilledunder reduced pressure to obtain the desired optically activefluorine-containing compound represented by the above formula (6) or(7).

[0062] In the processes of the present invention, the optically active2,3-epoxy-2-(trifluoromethyl)propionic acid benzyl ester represented bythe above formula (3) or (4), to be used for the hydrogenation reaction,is not necessarily highly pure and, for example, may be used in the formof a composition containing cumyl alcohol as a decomposition product ofcumene hydroperoxide, an optically active 1,1′-bi-2-naphthol,triphenylphosphine oxide, etc. After completion of the asymmetricepoxidizing reaction of the α,α,α,-trifluoromethacrylic acid benzylester, whereby the hydrogenation reaction will proceed under theabove-mentioned reaction conditions. In such a case, post-treatment isnot particularly limited, but usually, the catalyst is filtered off, thesolvent is distilled off under reduced pressure, and then ethyl acetate,water and sodium hydrogen carbonate are added, followed by stirring andliquid separation, whereupon the aqueous layer is acidified with e.g.hydrochloric acid and extracted with ethyl acetate, whereby the desiredoptically active fluorine-containing compound represented by the aboveformula (6) or (7) can be obtained.

[0063] By reducing the optically active fluorine-containing compoundrepresented by the above formula (6) of the present invention with ametal hydride, it is possible to produce(R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid. Likewise, byreducing the optically active fluorine-containing compound representedby the above formula (7) with a metal hydride, it is possible to produce(S)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid.

[0064] In the processes of the present invention, the metal hydride tobe used for the reduction reaction is not particularly limited. However,specifically, sodium boron hydride, sodium boron trimethoxy hydride,sodium boron cyanide hydride, sodium boron triacetoxy hydride, lithiumboron hydride, lithium boron tri-s-butyl hydride, lithium boron triethylhydride, lithium boron tricyamyl hydride, potassium boron hydride,potassium boron tri-s-butyl hydride, potassium boron tricyamyl hydride,zinc boron hydride, calcium boron hydride, lithium aluminum hydride,lithium aluminum trimethoxy hydride, lithium aluminum tri-t-butoxyhydride, sodium aluminum bis(2-methoxyethoxy) hydride or aluminumdiisobutyl hydride, may, for example, be mentioned. Among them,preferred is aluminum diisobutyl hydride.

[0065] In the processes of the present invention, the amount of themetal hydride to be used for the reduction reaction is usually from 1 to5 equivalents to the optically active2,3-epoxy-2-(trifluoromethyl)propionic acid represented by the aboveformula (6) or (7).

[0066] In the processes of the present invention, the solvent useful forthe reduction reaction varies depending upon the type of the metalhydride and is not particularly limited so long as it is inert to thereaction. Specifically, an alcohol such as methanol or ethanol, an ethersuch as THF, diethyl ether or diisopropyl ether, an aliphatichydrocarbon such as hexane or heptane, a halogenated hydrocarbon such asdichloromethane or chloroform, or an aromatic hydrocarbon such asbenzene or toluene, may, for example, be mentioned. For example, in acase where aluminum diisobutyl hydride is used as the metal hydride,toluene, hexane or the like, or a halogenated hydrocarbon mixturethereof with a dichloromethane or the like, is preferred.

[0067] In the processes of the present invention, the reactiontemperature and the reaction time in the reduction reaction are notparticularly limited, but the reaction will usually be completed withina range of from −100° C. to 20 C. in from 1 to 24 hours.

[0068] In the processes of the present invention, post-treatment afterthe reduction reaction is not particularly limited, but it is commonthat methanol is dropwise added at −80° C. or lower to terminate thereaction, and the reaction solution is acidified with e.g. hydrochloricacid, and then sodium chloride is added and extracted with ethyl etherto obtain (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid or(S)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid. The obtainedoptically active 3,3,3-trifluoro-2-hydroxy-2-methylpropinic acid can berecrystallized from a solvent such as toluene to bring the opticalpurity usually to a level of 99.9% ee or higher.

[0069] The present invention provides novel optically activefluorine-containing compounds and thus is industrially useful.

[0070] Among the derivatives of the present invention, the opticallyactive 2,3-epoxy-2-(trifluoromethyl)propionic acid benzyl esterrepresented by the above formula (3) or (4) is capable of easily andefficiently producing optically active3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid without using anoptical resolution agent or enzyme, and accordingly, the productionprocess of the present invention is a process which is simple andefficient as compared with the conventional processes and which issuitable for mass production, and thus it is industrially very useful.

[0071] Now, the present invention will be described in further detailwith reference to Examples. However, it should be understood that thepresent invention is by no means restricted to such specific Examples.The following instruments were used for the analyses of the compounds.

[0072]¹H-NMR and ¹³C-NMR Measurements

[0073] Carried out by means of Gemini-200, manufactured by Varian.

[0074] Infrared Absorption Measurement

[0075] Carried out by means of 2000FT-IR, manufactured by Perkin Elmer.

[0076] Elemental Analysis

[0077] C, H: Carried out by means of 2400IICH, manufactured by PerkinElmer.

[0078] F: Carried out by means of HPLC; column: TSKgel IC-Anion-PWXLPEEK (4.6 mm ID×750 mm), manufactured by Tosoh Corporation; eluent: 1.3mM gluconic acid-borax buffer; detector: electrical conductivity tester.

[0079] Mass Analysis

[0080] Carried out by means of M-80B, manufactured by Hitachi, Ltd.

[0081] Measurement of Specific Rotation

[0082] Carried out by means of SEPA-300, manufactured by HORIBA, Ltd.

REFERENCE EXAMPLE 1

[0083] Preparation of α,α,α-trifluoromethacrylic acid benzyl ester

[0084] Into a 500 ml two-necked round-bottomed flask equipped with acondenser and a stirrer, α,α,α-trifluoromethacrylic acid (154.0 g, 1.10mol) and thionyl chloride (170.1 g, 1.43 mol) were charged and refluxedfor 5 hours. By distillation, α,α,α-trifluoromethacrylic acid chloride(92.6 g) having a boiling point of from 88 to 92° C., was obtained(yield: 53%). Further, as a by-product, α,α,α-trifluoromethacrylic acidanhydride (34.0 g) having a boiling point of 106° C./31 mmHg wasobtained (yield: 24%).

[0085] Into a 1,000 ml three-necked round-bottomed flask equipped with adropping funnel and a stirrer, benzyl alcohol (54.6 g, 0.51 mol) anddiethyl ether (600 ml) were charged, and then, theα,α,α-trifluoromethacrylic acid chloride (80.0 g, 0.51 mol) obtained asdescribed above, was dropwise added at −40° C., and then a mixturecomprising triethylamine (56.2 g, 0.56 mol) and diethyl ether (100 ml)was dropwise added. The mixture was stirred at −40° C. for one hour andthen further stirred at 0° C. for one hour. To the reaction solution, asaturated ammonium chloride aqueous solution was added, and then,extracted with diethyl ether and dried over anhydrous magnesium sulfate,and the solvent was distilled off under reduced pressure. The residuewas purified by silica gel column chromatography (hexane/ethylacetate=9/1:vol/vol) to obtain α,α,α-trifluoromethacrylic acid benzylester (95.3 g) (yield: 82%).

[0086] Analytical Results

[0087]¹H-NMR(200 MHz,CDCl₃) δ 7.37-7.29(m, 5H), 6.70-6.67(m, 1H),6.38-6.37(m, 1H), 5.25(s, 2H)

EXAMPLE 1

[0088] Preparation of (S)-2,3-epoxy-2-trifluoromethylpropionic acidbenzyl ester

[0089] A 2,000 ml three-necked round-bottomed flask having a droppingfunnel and a stirrer, was flushed with nitrogen, and then, molecularsieves 4A (46.3 g, product preliminarily dried under reduced pressure at180° C. for 4 hours), (R)-1,1′-bi-2-naphthol (7.29 g, 25.5 mmol),triphenylphosphine oxide (19.3 g, 69.5 mmol) and THF (250 ml) wereadded. Stirring was carried out for 5 minutes for dissolution, and thena THF solution (250 ml) of lanthanum triisopropoxide (7.32 g, 23.2 mmol)was added, followed by stirring at room temperature for one hour. Cumenehydroperoxide (7.06 g, 46.4 mmol) was added, followed by furtherstirring at room temperature for two hours to prepare a catalyst.

[0090] After confirming that the reaction solution became green, thereaction solution was cooled to −20° C. Cumene hydroperoxide (89.8 g,0.59 mol) was added, and then a THF (500 ml) solution ofα,α,α-trifluoromethacrylic acid benzyl ester (106.6 g, 0.46 mol) wasdropwise added over a period of one hour from the dropping funnel. Afterstirring at −20° C. for 12 hours, disappearance of the raw material wasconfirmed by ¹H-NMR.

[0091] A saturated ammonium chloride aqueous solution (300 ml) and a 5%sodium hydrogen sulfite aqueous solution (200 ml) were added toterminate the reaction, whereupon insoluble matters were filtered off bycelite filtration, followed by liquid separation. The organic layer wasconcentrated and then, starting point components were removed by silicagel column chromatography (hexane/ethyl acetate=3/1:vol/vol). Furtherpurification was carried out by silica gel column chromatography(hexane/ethyl acetate=9/1:vol/vol) to obtain(S)-2,3-epoxy-2-trifluoromethylpropionic acid benzyl ester (104.7 g)(yield: 92%, optical purity: 78 ee %). Here, the measurement of theoptical purity was carried out under the following conditions.

[0092] Column: CHIRALCEL OD-H (4.6 mmID×250 mm), manufactured by Daicel.

[0093] Eluent: hexane/isopropanol=9/1(vol/vol)

[0094] Flow rate: 1.0 ml/min

[0095] Detector: UV=254 nm

[0096] Retention time: 10.3 min (S), 11.2 min(R).

[0097] The (S)-2,3-epoxy-2-trifluoromethylpropionic acid benzyl esterobtained in Example 1 was isolated and purified by means of an opticalresolution column (CHIRALCEL OD-H, manufactured by Daicel) and analyzed.The physical property values are shown below.

[0098] Analytical Results

[0099]¹H-NMR(200 MHz,CDCl₃) δ 7.48-7.26(m, 5H), 5.36-5.22(m, 2H),3.27-3.19(m, 2H)

[0100]¹³C-NMR(50 MHz,CDCl₃) δ 163.40, 134.15, 128.74, 128.70, 128.19,121.45(q, J=276.5 Hz), 68.30, 53.94(q, J=37.6 Hz), 49.02

[0101] IR (KBr: γ cm⁻¹) 3037, 2965, 1755, 1499, 1457, 1389, 1331, 1237,1179, 1148, 1078, 1030, 958, 870, 782, 752, 696

[0102] Elemental analysis: C,53.67; H,3.68; F,23.42 (Calc.: C,53.64;H,3.74; F,23.15). MASS (m/z) 246 (M+) Specific rotation (α)_(D) ²⁵=9.8°(C=2.0, methanol)

EXAMPLE 2

[0103] Preparation of (R)-2,3-epoxy-2-trifluoromethylpropionic acidbenzyl ester

[0104] The reaction was carried out in the same manner as in Example 1by using (S)-1,1′-bi-2-naphthol instead of (R)-1,1′-bi-2-naphthol, toobtain (R)-2,3-epoxy-2-trifluoromethylpropionic acid benzyl ester(yield: 90%, optical purity: 78 ee %). ¹H and ¹³C-NMR and IR spectrumdata were the same as shown in Example 1.

[0105] Analytical Results

[0106] Elemental analysis: C,53.45; H,3.78; F,2,3.09 (Calc.: C,53.64;H,3.74; F,23.15).

[0107] Specific rotation (α)_(D) ²⁵=9.8° (C=2.0, methanol)

EXAMPLE 3

[0108] Preparation of (S)-2,3-epoxy-2-trifluoromethylpropionic acid

[0109] Into a 500 ml three-necked round-bottomed flask equipped with astirrer, (S)-2,3-epoxy-2-trifluoromethylpropionic acid benzyl ester(20.9 g, 84.9 mmol, 99 ee %) was charged, and 180 ml of methanol wasadded for dissolution. Platinum oxide (1.63 g) was added, and then, thereaction system was substituted by hydrogen. After stirring at roomtemperature for 4 hours, platinum oxide was filtered off. The solventwas distilled off under reduced pressure, whereupon(S)-2,3-epoxy-2-trifluoromethylpropionic acid (11.9 g) was obtained(yield: 90%).

[0110] Analytical Results

[0111]¹H-NMR(CDCl₃) δ 9.28(br, 1H), 3.36-3.25(m, 2H)

[0112]¹³C-NMR(CDCl₃) δ 168.76, 121.25(q, J=275.6 Hz), 53.71(q, J=38.5Hz)

[0113] IR (KBr: γ cm⁻¹) 3528, 2928, 1744, 1636, 1388, 1318, 1259, 1179,1090, 961, 875, 758, 684

[0114] Elemental analysis: C,30.78; H,1.94; F,36.38; (Calc: C,30.59;H,1.80; F,36.52).

[0115] MASS (m/z) 157 ((M+H)+)

[0116] Specific rotation (α)_(D) ²⁵=10.9° (C=2.0, methanol)

EXAMPLE 4

[0117] Preparation of (R)-2,3-epoxy-2-trifluoromethylpropionic acid

[0118] The reaction was carried out under the same conditions as inExample 3 by using (R)-2,3-epoxy-2-trifluoromethylpropionic acid benzylester instead of (S)-2,3-epoxy-2-trifluoromethylpropionic acid benzylester, to obtain (R)-2,3-epoxy-2-trifluoromethylpropionic acid (yield:93%). The ¹H and ¹³C-NMR and IR spectrum data thereof were the same asshown in Example 3.

[0119] Analytical Results

[0120] Elemental analysis: C,30.67; H,1.72; F,36.71 (Calc.: C,30.59;H,1.80; F,36.52).

[0121] Specific rotation (α)_(D) ²⁵=−10.9° (C=2.0, methanol)

EXAMPLE 5

[0122] Preparation of (S)--3,3,3-trifluoro-2-hydroxy-2-methylpropionicacid

[0123] Into a 500 ml three-necked round-bottomed flask equipped with astirrer, a 1.0 M aluminum diisobutyl hydride/hexane solution (2400 ml,2.40 mol) was charged in a nitrogen atmosphere. This solution was cooledto −80° C. A dichloromethane (600 g) solution of(S)-2,3-epoxy-2-trifluoromethylpropionic acid (149.82 g, 0.96 mol) wasadded over a period of two hours from a dropping funnel. After stirringat −70° C. for one hour, stirring was carried out at −50° C. for 6hours. The reaction solution was cooled to −80° C., and a mixed solutionof methanol (100 g) and dichloromethane (100 g) was dropwise added overa period of two hours to terminate the reaction. The reaction solutionwas dropwise added over a period of two hours to 1800 ml of a 18% HClaqueous solution cooled to 0° C., and then, 160 g of sodium chloride wasadded. The mixture was extracted twice with 500 ml of diethyl ether, andthe solvent was distilled off to obtain(S)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (98.6 g) (yield:65%). This was recrystallized twice from toluene (400 ml) to obtain(S)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (51.6 g) having anoptical purity of 99.9 ee % (yield: 34%). This product shows the same ¹Hand ¹³C-NMR and IR spectrum data as the already reported(S)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid and therefore wasdetermined to be (S)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid.

[0124] Here, the measurement of the optical purity was carried out asfollows. To the obtained crystals, an ether solution of diazomethane wasadded for methylesterification, and this solution was analyzed by gaschromatography (GC) under the following conditions, whereupon theoptical purity was calculated.

[0125] Column: CP-Chiracil-Dex CB (0.25 mm×25 m), manufactured byChrompak Company.

[0126] Column temperature: 70° C.

[0127] Detector: FID

[0128] Analytical Results

[0129] Specific rotation (α)_(D) ²⁵=−18.9° (C=4.0, methanol)

EXAMPLE 6

[0130] Preparation of (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionicacid

[0131] The reaction was carried out under the same conditions as inExample 5 by using (R)-2,3-epoxy-2-trifluoromethylpropionic acid insteadof (S)-2,3-epoxy-2-trifluoromethylpropionic acid, to obtain(R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (yield: 36%). Thisproduct shows the same ¹H and ¹³C-NMR and IR spectrum data as thealready reported (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acidand therefore was determined to be(R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid.

[0132] Analytical Results

[0133] Specific rotation (α)_(D) ²⁵=18.9° (C=4.0, methanol)

REFERENCE EXAMPLE 2

[0134] Preparation of α,α,α-trifluoromethacrylic acid phenyl ester

[0135] In the same manner as in Reference Example 1,α,α,α-trifluoromethacrylic acid phenyl ester (10.3 g, 47.7 mmol, yield:63%) was obtained from α,α,α-trifluoromethacrylic acid chloride (10 g,63.0 mmol), phenol (6.5 g, 69.0 mmol) and triethylamine (7.66 g, 75.7mmol).

[0136] Analytical Results

[0137]¹H-NMR (200 MHz, CDCl₃) δ 7.42-7.14 (m, 5H), 6.94-6.92(m, 1H),6.61-6.60 (m, 1H)

EXAMPLE 7

[0138] Preparation of (S)-2,3-epoxy-2-trifluoromethylpropionic acidphenyl ester

[0139] A 500 ml three-necked round-bottomed flask equipped with adropping funnel and a stirrer was flushed with nitrogen, and then,molecular sieves 4A (3.7 g, product preliminarily dried under reducedpressure at 180° C. for 4 hours), (R)-1,1′-bi-2-naphthol (529.8 mg, 1.85mmol), triphenylphosphine oxide (1.54 g, 5.6 mmol) and THF (90 ml) wereadded. Stirring was carried out for 5 minutes for dissolution, and thena THF solution (90 ml) of lanthanum triisopropoxide (585 mg, 1.85 mmol)was added, followed by stirring at room temperature for one hour. Cumeneperoxide (740 μm, 80% pure product, 3.9 mmol) was added, followed byfurther stirring at room temperature for two hours to prepare acatalyst.

[0140] After confirming that the reaction solution became green, thereaction solution was cooled to −20° C. Cumene hydroperoxide (8.4 g, 80%pure product, 44.1 mmol) was added, and then, a THF (90 ml) solution ofα,α,α-trifluoromethacrylic acid phenyl ester (8.0 g, 37.0 mmol) wasdropwise added over a period of one hour from a dropping funnel. Afterstirring at −20° C. for 12 hours, disappearance of the raw material wasconfirmed by ¹H-NMR.

[0141] A saturated ammonium chloride aqueous solution (50 ml) and a 5%sodium hydrogen sulfite aqueous solution (10 ml) were added to terminatethe reaction, and then, insoluble matters were filtered off by celitefiltration, followed by liquid separation. The organic layer wasconcentrated, and then starting point components were removed by silicagel column chromatography (hexane/ethyl acetate=3/1:vol/vol). Furtherpurification was carried out by silica gel column chromatography(hexane/ethyl acetate=9/1:vol/vol), to obtain(S)-2,3-epoxy-2-trifluoromethylpropionic acid phenyl ester (7.2 g, 31.0mmol) (yield: 84%, optical purity: 79 ee %). Here, the measurement ofthe optical purity was carried out under the following conditions.

[0142] Analytical Results

[0143]¹H-NMR(200 MHz, CDCl₃) δ 7.46-7.13(m, 5H), 3.46-3.41 (m, 1H), 3.36(d, 1H, J=6.0 Hz)

[0144]¹³C-NMR(500 MHz, CDCl₃) δ 162.17, 149.57, 129.35, 125.86, 121.42(q, J=275.9 Hz), 120.84, 54.13(q, J=37.8 Hz), 49.33

[0145] IR (KBr: γ cm⁻¹) 3511, 3068, 1774, 1592, 1493, 1458, 1386, 1336,1235, 1187, 1081, 1064, 1024, 1004, 959, 924, 877, 833, 747, 700, 687

[0146] Elemental analysis: C,51.56; H,3.18; F,24.47 (Calc: C,51.74;H,3.04; F,24.55). MASS (m/z) 232 (M+) Specific rotation (α)_(D) ²⁵=0.9°(C=2.0, methanol)

EXAMPLE 8

[0147] Preparation of (S)-2,3-epoxy-2-trifluoromethylpropionic acid

[0148] Into a 100 ml three-necked round-bottomed flask equipped with adropping funnel and a stirrer, the(S)-2,3-epoxy-2-trifluoromethylpropionic acid phenyl ester (7.2 g, 31.0mmol) obtained in Example 7, methanol (20 ml) and water (20 ml) werecharged and cooled to 0° C. on an ice bath, whereupon 3N sodiumhydroxide aqueous solution (30 ml, 90 mmol) was dropwise added over aperiod of one hour by means of the dropping funnel, and stirring wasfurther carried out at the same temperature for one hour. Aftercompletion of the reaction, methanol was distilled off, followed byextraction with diisopropyl ether (30 ml×twice). Then, hydrochloric acidwas added to adjust the pH to 3, followed by extraction with ethylacetate (30 ml×3 times). The obtained organic layer was dried overanhydrous magnesium sulfate, followed by filtration and concentration toobtain the desired (S)-2,3-epoxy-2-trifluoromethylpropionic acid (4.17g, 26.7 mmol, yield: 87%, optical purity: 78% ee).

REFERENCE EXAMPLE 3

[0149] Preparation of α,α,α-trifluoromethacrylic acid (p-chloroanilide)

[0150] In the same manner as in Reference Example1,α,α,α-trifluoromethacrylic acid (m-chloroanilide) (14.5 g, 58.0 mmol,yield: 92%) was obtained from α,α,α-trifluoromethacrylic acid chloride(10 g, 63.0 mmol), m-chloroaniline (8.9 g, 69.4 mmol) and triethylamine(7.00 g, 69.4 mmol).

[0151] Analytical Results

[0152]¹H-NMR (200 MHz, CDCl₃) δ 7.68-7.13 (m, 4H), 6.68-6.65 (m, 1H),6.38-6.37 (m, 1H)

EXAMPLE 9

[0153] Preparation of (S)-2,3-epoxy-2-trifluoromethylpropionic acid(m-chloroanilide)

[0154] A 1,000 ml three-necked round-bottomed flask equipped with adropping funnel and a stirrer was flushed with nitrogen, and then,molecular sieves 4A (3.70 g, product preliminarily dried under reducedpressure at 180° C. for 4 hours), (R)-1,1′-bi-2-naphthol (2.11 g, 7.37mmol), triphenylphosphine oxide (6.15 g, 22.1 mmol) and THF (100 ml)were added. Stirring was carried out for 5 minutes for dissolution, andthen, a THF solution (100 ml) of lanthanum triisopropoxide (2.33 g, 7.37mmol) was added, followed by stirring at room temperature for one hour.Cumene hydroperoxide (2.80 g, 80% pure product, 14.7 mmol) was added,followed by further stirring at room temperature for two hours, toprepare a catalyst.

[0155] After confirming that the reaction solution became green, thereaction solution was cooled to −20° C. Cumene hydroperoxide (6.31 g,80% pure product, 33.16 mol) was added, and then a THF (100 ml) solutionof α,α,α-trifluoromethacrylic acid (m-chloroanilide) (9.20 g, 36.8 mmol)was dropwise added over a period of one hour from the dropping funnel.After stirring at −20° C. for 12 hours, disappearance of the rawmaterial was confirmed by ¹H-NMR.

[0156] A saturated ammonium chloride aqueous solution (200 ml) and a 5%sodium hydrogen sulfite aqueous solution (150 ml) were added toterminate the reaction, whereupon insoluble matters were filtered off bycelite filtration, followed by liquid separation. The organic layer wasconcentrated and then, starting point components were removed by silicagel column chromatography (hexane/ethyl acetate=3/1:vol/vol). Furtherpurification was carried out by silica gel column chromatography(hexane/ethyl acetate=9/1:vol/vol), to obtain(S)-2,3-epoxy-2-trifluoromethylpropionic acid (m-chloroanilide) (7.54 g,28.5 mmol) (yield: 77%, optical purity: 84 ee %).

[0157] Analytical Results

[0158]¹H-NMR(200 MHz, CDCl₃) δ 7.68-7.10(m, 4H), 4.12 (d, 1H, J=4.4 Hz),3.19 (d, 1H, J=4.4 Hz)

[0159] Elemental analysis: C,54.12; H,2.87; N,5.19; C,113.19, F,21.35(Calc: C,45.22; H,2.66; N,5.27; C,113.35; F,21.46). MASS (m/z) 265 (M+)

[0160] Specific rotation (α)_(D) ²⁵=7.3° (C=2.0, methanol)

EXAMPLE 10

[0161] Preparation of (S)-2,3-epoxy-2-trifluoromethylpropionic acid

[0162] Into a 300 ml round-bottomed flask equipped with a stirrer, the(S)-2,3-epoxy-2-trifluoromethylpropionic acid (m-chloroanilide) (7.54 g,28.5 mmol) obtained in Example 9, methanol (100 ml) and 35% hydrochloricacid (25 ml) were charged and stirred at room temperature for 4 days.

[0163] After completion of the reaction, methanol was distilled off,followed by extraction with ethyl acetate (30 ml×three times). Theobtained organic layers were put together and washed with 1Nhydrochloric acid (20 ml×twice), followed by drying over anhydrousmagnesium sulfate, filtration and concentration to obtain the desired(S)-2,3-epoxy-2-trifluoromethylpropionic acid (2.75 g, 17.6 mmol, yield:62%, optical purity: 84% ee).

[0164] The entire disclosure of Japanese Patent Application No.2002-340758 filed on Nov. 25, 2002 including specification, claims andsummary is incorporated herein by reference in its entirety.

What is claimed is:
 1. An optically active fluorine-containing compoundrepresented by the following formula (1):

wherein A is an oxygen atom, a sulfur atom or an NH group, and R¹ is amethyl group, an ethyl group, a C₃₋₁₀ linear, branched or cyclic alkylgroup, a C₆₋₂₀ aromatic group, a C₆₋₂₀ aromatic group having hydrogen onthe aromatic ring optionally substituted by a halogen atom, a C₆₋₂₀aromatic group having hydrogen on the aromatic ring optionallysubstituted by a methyl group, a C₆₋₂₀ aromatic group having hydrogen onthe aromatic ring optionally substituted by an ethyl group, a C₆₋₂₀aromatic group having hydrogen on the aromatic ring optionallysubstituted by a C₃₋₆ linear, branched or cyclic alkyl group, a C₆₋₂₀aromatic group having hydrogen on the aromatic ring optionallysubstituted by a methoxy group, a C₆₋₂₀ aromatic group having hydrogenon the aromatic ring optionally substituted by an ethoxy group, a C₆₋₂₀aromatic group having hydrogen on the aromatic ring optionallysubstituted by a C₃₋₆ linear, branched or cyclic alkyloxy group, a C₅₋₁₉heteroaromatic group, a C₅₋₁₉ heteroaromatic group having hydrogen onthe aromatic ring optionally substituted by a halogen atom, a C₅₋₁₉heteroaromatic group having hydrogen on the aromatic ring optionallysubstituted by a methyl group, a C₅₋₁₉ heteroaromatic group havinghydrogen on the aromatic ring optionally substituted by an ethyl group,a C₅₋₁₉ heteroaromatic group having hydrogen on the aromatic ringoptionally substituted by a C₃₋₆ linear, branched or cyclic alkyl group,a C₅₋₁₉ heteroaromatic group having hydrogen on the aromatic ringoptionally substituted by a methoxy group, a C₅₋₁₉ heteroaromatic grouphaving hydrogen on the aromatic ring optionally substituted by an ethoxygroup, a C₅₋₁₉ heteroaromatic group having hydrogen on the aromatic ringoptionally substituted by a C₃₋₆ linear, branched or cyclic alkyloxygroup, a benzyl group, a benzyl group having hydrogen on the aromaticring optionally substituted by a halogen atom, a benzyl group havinghydrogen on the aromatic ring optionally substituted by a methyl group,a benzyl group having hydrogen on the aromatic ring optionallysubstituted by an ethyl group, a benzyl group having hydrogen on thearomatic ring optionally substituted by a C₃₋₆ linear, branched orcyclic alkyl group, a 2-phenylethyl group, or a C₃₋₁₀ linear, branchedor cyclic alkyl group having a C₆₋₂₀ aromatic group bonded thereto, orby the following formula (2):

wherein A and R¹ are as defined above.
 2. The optically activefluorine-containing compound according to claim 1, wherein in theformula (1) or (2), A is an oxygen atom or NH group, and R¹ is atert-butyl group, a phenyl group, a phenyl group having hydrogen on thearomatic ring substituted by a halogen atom, or a benzyl group.
 3. Anoptically active fluorine-containing compound represented by thefollowing formula (3) or (4):


4. A process for producing an optically active fluorine-containingcompound as defined in claim 1, which comprises asymmetricallyepoxidizing an (α,α,α-trifluoromethacrylic acid derivative representedby the following formula (5):

wherein A is an oxygen atom, a sulfur atom or an NH group, and R¹ is amethyl group, an ethyl group, a C₃₋₁₀ linear, branched or cyclic alkylgroup, a C₆₋₂₀ aromatic group, a C₆₋₂₀ aromatic group having hydrogen onthe aromatic ring optionally substituted by a halogen atom, a C₆₋₂₀aromatic group having hydrogen on the aromatic ring optionallysubstituted by a methyl group, a C₆₋₂₀ aromatic group having hydrogen onthe aromatic ring optionally substituted by an ethyl group, a C₆₋₂₀aromatic group having hydrogen on the aromatic ring optionallysubstituted by a C₃₋₆ linear, branched or cyclic alkyl group, a C₆₋₂₀aromatic group having hydrogen on the aromatic ring optionallysubstituted by a methoxy group, a C₆₋₂₀ aromatic group having hydrogenon the aromatic ring optionally substituted by an ethoxy group, a C₆₋₂₀aromatic group having hydrogen on the aromatic ring optionallysubstituted by a C₃₋₆ linear, branched or cyclic alkyloxy group, a C₅₋₁₉heteroaromatic group, a C₅₋₁₉ heteroaromatic group having hydrogen onthe aromatic ring optionally substituted by a halogen atom, a C₅₋₁₉heteroaromatic group having hydrogen on the aromatic ring optionallysubstituted by a methyl group, a C₅₋₁₉ heteroaromatic group havinghydrogen on the aromatic ring optionally substituted by an ethyl group,a C₅₋₁₉ heteroaromatic group having hydrogen on the aromatic ringoptionally substituted by a C₃₋₆ linear, branched or cyclic alkyl group,a C₅₋₁₉ heteroaromatic group having hydrogen on the aromatic ringoptionally substituted by a methoxy group, a C₅₋₁₉ heteroaromatic grouphaving hydrogen on the aromatic ring optionally substituted by an ethoxygroup, a C₅₋₁₉ heteroaromatic group having hydrogen on the aromatic ringoptionally substituted by a C₃₋₆ linear, branched or cyclic alkyloxygroup, a benzyl group, a benzyl group having hydrogen on the aromaticring optionally substituted by a halogen atom, a benzyl group havinghydrogen on the aromatic ring optionally substituted by a methyl group,a benzyl group having hydrogen on the aromatic ring optionallysubstituted by an ethyl group, a benzyl group having hydrogen on thearomatic ring optionally substituted by a C₃₋₆ linear, branched orcyclic alkyl group, a 2-phenylethyl group, or a C₃₋₁₀ linear, branchedor cyclic alkyl group having a C₆₋₂₀ aromatic group bonded thereto. 5.The process for producing an optically active fluorine-containingcompound according to claim 4, wherein in the formula (5), A is anoxygen atom, and R is a tert-butyl group, a phenyl group, a phenyl grouphaving hydrogen on the aromatic ring substituted by a halogen atom, or abenzyl group.
 6. The process for producing an optically activefluorine-containing compound according to claim 4, wherein in theformula (5), A is an oxygen atom, and R¹ is a benzyl group.
 7. Theprocess for producing an optically active fluorine-containing compoundaccording to claim 4, wherein the α,α,α-trifluoromethacrylic acidderivative represented by the formula (5) is subjected to the asymmetricepoxidizing reaction in the presence of a catalyst comprising (A) a rareearth metal alkoxide, (B) optically active 1,1′-bi-2-naphthol, (C)triphenylphosphine oxide and (D) cumene hydroperoxide or tert-butylhydroperoxide.
 8. The process for producing an optically activefluorine-containing compound according to claim 7, wherein (A) the rareearth metal alkoxide is a lanthanoid triisopropoxide.
 9. The process forproducing an optically active fluorine-containing compound according toclaim 7, wherein (A) the rare earth metal alkoxide is lanthanumtriisopropoxide.
 10. An optically active fluorine-containing compoundrepresented by the following formula (6) or (7):


11. A process for producing the optically active fluorine-containingcompound represented by the formula (6):

which comprises hydrolyzing the optically active fluorine-containingcompound represented by the formula (1) in claim
 1. 12. A process forproducing the optically active fluorine-containing compound representedby the formula (7):

which comprises hydrolyzing the optically active fluorine-containingcompound represented by the formula (2) in claim
 1. 13. A process forproducing the optically active fluorine-containing compound representedby the formula (6):

which comprises hydrolyzing or hydrogenating the optically activefluorine-containing compound represented by the formula (3) in claim 3.14. A process for producing the optically active fluorine-containingcompound represented by the formula (7):

which comprises hydrolyzing or hydrogenating an optically activefluorine-containing compound represented by the formula (4) in claim 3.15. A process for producing(R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid, which comprisesreacting the optically active fluorine-containing compound representedby the formula (6) in claim 10, with a metal hydride.
 16. A process forproducing (S)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid, whichcomprises reacting the optically active fluorine-containing compoundrepresented by the formula (7) in claim 10, with a metal hydride.